WO2001051061A1 - Derives de macrolides de polyene, preparation et utilisations correspondantes - Google Patents

Derives de macrolides de polyene, preparation et utilisations correspondantes Download PDF

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WO2001051061A1
WO2001051061A1 PCT/US2001/001294 US0101294W WO0151061A1 WO 2001051061 A1 WO2001051061 A1 WO 2001051061A1 US 0101294 W US0101294 W US 0101294W WO 0151061 A1 WO0151061 A1 WO 0151061A1
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Prior art keywords
polyene macrolide
polyene
acid
macrolide
carbohydrate
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PCT/US2001/001294
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English (en)
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Christopher J. Baldwin
Conway Cheng Chang
Binh T. Dang
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Intrabiotics Pharmaceuticals, Inc.
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Priority to EP01903072A priority Critical patent/EP1278527A4/fr
Priority to CA002394833A priority patent/CA2394833A1/fr
Priority to AU30935/01A priority patent/AU780724B2/en
Priority to JP2001551485A priority patent/JP2003519662A/ja
Publication of WO2001051061A1 publication Critical patent/WO2001051061A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates generally to derivatives of polyene macrolides.
  • the present invention relates to water soluble glycosyl derivatives of polyene macrolides useful for treating or preventing topical and/or systemic fungal infections in humans and animals.
  • polyene macrolides are known that have antifungal properties useful in treating topical and/or systemic fungal infections.
  • examples of these polyene macrolides include amphotericin B, aureofacin, candicidin, candidin, levorin, mycoheptin, nystatin, perimycin, pimaricin, polyfiingin, rimocidin and trichomycin.
  • amphotericin B aureofacin
  • candicidin candicidin
  • candidin candidin
  • levorin mycoheptin
  • nystatin perimycin
  • pimaricin polyfiingin
  • rimocidin and trichomycin.
  • these compounds due to their macrocyclic nature and amphoteric character, these compounds generally have poor solubility in aqueous solutions, which limits their usefulness in the treatment of systemic fungal infections.
  • these polyene macrolides exhibit undesirable toxic properties when used systemically.
  • amphotericin B methyl ester AME
  • amphotericin B methyl ester AME
  • AME amphotericin B methyl ester
  • U.S. Patent No. 4,365,058 to Falkowski et al. teaches esters of polyene macrolides that are substituted at the sugar amino group with non-sugar substituents.
  • U.S. Patent No. 4,783,527 to Falkowski et al. teaches amides of polyene macrolides substituted at the amide nitrogen with an alkyl, isoalkyl or heterocyclic group.
  • U.S. Patent No. 5,314,999 to Seman et al. teaches polyene macrolides substituted at the N position with a 1 -amino- 1-deoxyketose group, which itself may be further substituted.
  • U.S. Patent No. 5,942,495 to Borowski et al. teaches N-alkyl-N-glycosyl derivatives of polyene macrolides that are reported to have antifungal activity, form water soluble salts with acids and lower toxicity than other N-alkyl polyene macrolide derivatives.
  • the present invention provides a new class of polyene macrolide derivatives that exhibit su ⁇ risingly superior antifungal activity, increased water solubility and lower toxicity than amphotericin B (AmB) and amphotericin B methyl ester (AME).
  • the polyene macrolide derivatives of the invention comprise a "core" polyene macrolide backbone derived from any of a variety of polyene macrolides having two features: a carboxyl substituent and an amino sugar substituent.
  • the carboxyl substituent of the "core” is converted to an alkyl or arylalkyl ester, thioester or amide, and the amino group of the amino sugar is substituted with a carbohydrate residue, which may be a mono, oligo or polysaccharide.
  • the present invention provides polyene macrolide derivatives according to structural formula (I):
  • R 1 is a polyene macrolide backbone
  • CH 2 -R 2 is a carbohydrate residue, where the illustrated CH 2 includes the anomeric carbon of a terminal carbohydrate saccharide
  • R 3 is alkyl or arylalkyl; and X is O, S orNH.
  • the polyene macrolide derivatives are compounds according to structural formula (I), with the proviso that when R 1 is a polyene macrolide backbone derived from amphotericin B, X is O, and R 3 is methyl, lower alkanyl or lower alkyl, then R 2 is other than fructosyl.
  • the present invention provides methods for making these new polyene macrolide derivatives.
  • a parent polyene macrolide is reacted according to known methods to yield the corresponding alkyl or arylalkyl ester, thioester or amide.
  • the ester, thioester or amide is then reacted with an appropriate reducing sugar under Amadori rearrangement conditions to yield a new polyene macrolide derivative according to the invention.
  • the present invention provides pharmaceutical compositions including the new polyene macrolide derivatives, or pharmaceutically acceptable salts thereof, as well as methods for treating and/or preventing fungal infections in plants or animals, including humans.
  • the pharmaceutical compositions generally comprise one or more polyene macrolide derivatives of the invention and a pharmaceutically acceptable carrier, excipient or diluent. The choice of carrier, excipient or diluent will depend upon the mode of administration.
  • the method generally involves administering to a plant or animal, including a human, one or more of the polyene macrolide derivatives or pharmaceutical compositions of the invention in an amount effective to treat or prevent a fungal infection in the plant, animal or human.
  • the polyene macrolide derivatives or pharmaceutical compositions may be administered systemically or applied topically, depending on the nature of the fungal infection.
  • FIG. 1 shows the levels of Candida albicans in the kidneys of mice treated with various polyene macrolide derivatives of the present invention.
  • the present invention provides new gylcosyl derivatives of polyene macrolides (and/or pharmaceutically acceptable salts thereof), pharmaceutical compositions comprising these polyene macrolide derivatives, methods of making these polyene macrolide derivatives, and methods of using the new polyene macrolide derivatives and/or pharmaceutical compositions to treat and/or prevent fungal infections in both plants and animals, including humans.
  • polyene macrolide derivatives described herein provide significant advantages over traditional polyene macrolide antifungals.
  • the polyene macrolide derivatives of the present invention provide greater water solubility, lower toxicity, and greater potency than traditional polyene macrolide antifungals such as amphotericin B (AmB) and amphotericin B methyl ester (AME).
  • AmB amphotericin B
  • AME amphotericin B methyl ester
  • the compounds of the present invention are polyene macrolide derivatives according to structural formula (I):
  • R 1 is a polyene macrolide backbone
  • CH 2 -R 2 is a carbohydrate residue, where the illustrated CH 2 includes the anomeric carbon of a terminal carbohydrate saccharide;
  • R 3 is alkyl or arylalkyl
  • the polyene macrolides of the invention are derivatives of "core" polyene macrolides of a specific type.
  • the core polyene macrolides are of a type that have a carboxyl substituent and an amino sugar substituent, as exemplified by, for example, AmB and nystatin.
  • the carboxyl substituent of the core polyene macrolide is converted to an alkyl or arylalkyl ester, thioester, or amide, and the amino group of the amino sugar substituent is substituted with a carbohydrate residue.
  • the carbohydrate residue which is described in more detail below, is attached to the amino group via the anomeric carbon of a terminal saccharide unit.
  • polyene backbone R 1 may be derived from any known or later discovered polyene macrolide having carboxyl and amino sugar substituents.
  • the polyene macrolide from which R 1 is derived will have antifungal activity.
  • Non-limiting examples of polyene macrolides having these features from which polyene backbone R 1 may be derived include, but are not limited to, amphotericin A (AmA), amphotericin B (AmB), aureofacin, candicidin, candidin, levorin, mycoheptin, nystatin (including A[), partricin (A and B), pentamycin, perimycin, pimaricin, polyfiingin, rimocidin, and trichomycin.
  • Preferred classes of polyene backbones R 1 are those derived from AmB and nystatin. The structures of nystatin and AmB are as illustrated below, including citations referencing methods whereby these polyene macrolides may be obtained:
  • macrolide backbone R 1 includes the sugar moiety that is attached to the macrocyclic portion of core polyene macrolide. This sugar, which is an inherent part of the core polyene macrolide, is to be distinguished from the carbohydrate residue CH 2 -R 2 of formula (I), which is not contributed by the core polyene macrolide and constitutes one of the inventive features of the derivatives of formula (I).
  • polyene backbone R 1 derived from AmB is illustrated below, wherein the dashed lines indicate the atoms which are bonded to the XR 3 and CH 2 -R 2 substituents in the derivatives of formula (I), and the bolded NH group is the NH illustrated in formula (I):
  • the carbohydrate residue CH 2 -R 2 may be any number of saccharide units in length and, typically ranges from 1 to about 100 saccharide units.
  • the carbohydrate residue can be a monosaccharide, an oligo saccharide comprising from two to tens of saccharide units or a poly saccharide comprising from tens to 30, 40, 50, 60 or even more saccharide units.
  • the carbohydrate residue will be of a number of saccharide units such that it is relatively water soluble, such as a mono saccharide or an oligo saccharide.
  • carbohydrate residue CH 2 -R 2 may be a large, water insoluble polysaccharide and still retain antifungal activity.
  • Polyene macrolide derivatives including large polysaccharides for carbohydrate residue CH 2 -R 2 that have low water-solubility may be used topically or as antifungals in non-aqueous environments.
  • the carbohydrate residue may be a homopolymer, in which all saccharide units are the same, or it may be a heterpolymer comprising mixtures of different saccharide units.
  • the carbohydrate residue may be branched or linear, and, as will be discussed in more detail below, the saccharide units may be independently of one another, in a cyclic conformation, a linear conformation or a mixture of cyclic and linear conformations.
  • the saccharide units of the carbohydrate residue may be substituted with a variety of different substituents. These substituents may be used to impart the derivatives of the invention with desirable properties, such as, for example, improved water-solubility.
  • the carbohydrate residue CH 2 - R 2 is produced via an Amadori rearrangement of an appropriate reducing carbohydrate, typically a reducing sugar. Therefore, the carbohydrate residue CH 2 -R 2 has a different structure from the reducing carbohydrate used as a reactant in the Amadori rearrangement used to produce the polyene macrolide derivatives of formula (I).
  • the principles of the Amadori rearrangement reaction and the requirements of reducing carbohydrates that can undergo an Amadori rearrangement are well-known and well understood. Briefly, the rearrangement and the requirements of the reducing carbohydrates, exemplified with a monosaccharide, are illustrated below:
  • n is an integer from 0 up to virtually any number, where n is 0 only in open chain conformers;
  • R 10 is hydrogen, alkyl, alkylidene, cycloalkyl, arylalkyl, aryl, glycosyl or polymer, but not acyl or a strongly electron- withdrawing radical;
  • R 11 is hydrogen, alkyl, alkylidene, arylalkyl, but not aryl when R 10 is aryl and, in addition, the combination of R 10 + R 11 in the reacting amine should not sterically hinder the nitrogen atom;
  • R 13 is hydrogen, -CH 2 OH, -CH 3> -COOH, -CONHR, -COOM + , and the like.
  • Any reducing carbohydrate having these attributes can be used in an Amadori rearrangement to yield the polyene macrolide derivatives of the invention.
  • Skilled artisans will be able to select an appropriate reducing carbohydrate reactant to obtain a derivative according to formula (I) that has the desired carbohydrate residue CH 2 -R 2 .
  • TABLE 1 presents an exemplary list of reducing carbohydrates that are capable of undergoing an Amadori rearrangement that may be used to produce the compounds of the present invention. Other carbohydrates having appropriate properties will be apparent to those of skill in the art.
  • N-(2,3,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yl)-acetamide panose pectic acid rhamnose ribose salicin sorbose sulfanilamide-N4-D(L)-glucoside talose xylose
  • R 10 represents the polyene backbone R 1 .
  • the resultant carbohydrate residue produced by an Amadori rearrangement reaction may be in either a cyclic or linear conformation, or a mixture of cyclic and linear conformers. While in the preferred polyene macrolide derivatives illustrated herein the various carbohydrate residues added via the Amadori rearrangement are shown in their cyclic conformations, these illustrations are not intended in any way to limit the carbohydrate residue of the illustrated polyene macrolide derivatives, or of any polyene macrolide derivatives, described herein, to the cyclic forms. When the carbohydrate residue is a monosaccharide, it may be linear, cyclic or a mixture of linear and cyclic conformers.
  • each monosaccharide unit my be cyclic or linear, or a mixture of cyclic and linear conformers.
  • the polyene macrolide derivatives described herein may be in the form of pure compounds or in the form of mixtures of two or more different conformers. The only requirement is that the polyene macrolide derivative, whether a single compound or mixture of different conformers, have antifungal activity as described herein.
  • preferred monosaccharide carbohydrate residues CH 2 -R 2 include glucopyranose, mannopyranose, galactopyranose, fructopyranose, and tagatopyranose.
  • Preferred polysaccharide carbohydrate residues CH 2 -R 2 include 4-O-( ⁇ -D-galactopyranosyl)-D-fructopyranose, 4-O- ( ⁇ -D-glucopyranosyl)-D-fructopyranose, 4-O-( ⁇ -D-galactopyranosyl)-D-fructopyranose, 4- O-( ⁇ -D-gluco ⁇ yranosyl)-D-fructopyranose, sucrose, maltose, lactose, cellobiose, L- rhinnose and D-ribose.
  • these carbohydrate residues are attached to the polyene backbone amino sugar amino group via the anomeric carbon of a terminal monosaccharide unit.
  • R 3 may be an alkyl group or an arylalkyl group.
  • alkyl refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, ⁇ ropan-2-yl, cyclopropan-1-yl, prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl , prop-2-yn-l-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-yl, but-2-en-l-y
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon- carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.
  • Alkanyl refers to a saturated branched, straight-chain or cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butyanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-l-yl , prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl ; butenyls such as but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl , but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • Alkynyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-l-yl , prop-2-yn-l-yl, etc.; butynyls such as but-1-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl , etc.; and the like.
  • the alkyl group may comprise from 1 to 12 carbon atoms.
  • the alkyl group is a lower alkyl having from 1 to 6 carbon atoms.
  • the alkyl is (C ⁇ -C 3 ) alkanyl or alkenyl.
  • the most preferred alkyl groups are methyl and allyl, such that the compounds of formula (I) are methyl or allyl esters, methyl or allyl thioesters, or methyl or allyl amides.
  • R 3 may be an arylalkyl group.
  • arylalkyl refers to an alkyl group in which one of the alkyl hydrogens is replaced with an aryl substituent. Where specific levels of saturation of the alkyl portion of the arylalkyl group are intended, the nomenclature “arylalkanyl,” “arylalkenyl” and “arylalkynyl” is used, where “alkanyl,” alkenyl” and “alkynyl” are as previously defined.
  • Typical aryl substituents in the arylalkyl group include, but are not limited to, penta-2,4-dienyl, phenyl, naphthyl, and the like.
  • the arylalkyl may comprise from 6 to 26 carbon atoms.
  • the aryl portion of the arylalkyl group is phenyl or naphthyl and the alkyl portion is a lower alkyl. More preferably, the alkyl portion of the arylalkyl group is a lower alkanyl.
  • the most preferred arylalkyl group is benzyl, such that the compounds of formula (I) are benzyl esters, benzyl thioesters or benzyl amides.
  • Substituent X may be either O, S, or NH.
  • X is O or NH, with O being particularly preferred.
  • polyene macrolide derivatives according to the invention are compounds according to structural formula (I), with the proviso that when R 1 is a polyene macrolide backbone derived from amphotericin B, X is O, and R 3 is methyl, lower alkanyl or lower alkyl, then R 2 is other than fructosyl.
  • polyene macrolide derivatives of the invention are compounds according to formula (I), with the proviso that the compound is not the compound identified as N-fructosyl methyl ester AmB in Szponarski et al, 1988, Biochimica Biophysica Acta 938:97-106, at page 99 in Fig. 1, which for convenience is illustrated below:
  • glycosyl AmB methyl ester derivatives Another important class of polyene macrolide derivatives according to the invention include glycosyl AmB methyl ester derivatives.
  • glycosyl AmB methyl ester derivatives include glycosyl AmB methyl ester derivatives.
  • specific compounds are preferred:
  • the polyene backbone R 1 is illustrated with the stereochemistry of many of the chiral centers specified.
  • the specific structures depicted are those that have been reported in the literature for the involved polyene backbones, and are not intended as limiting. Thus, it will be understood that the illustrated structures are intended merely as a short-hand way to represent the actual compound, and to the extent it may be found at a later date these structural representations are incorrect, they are not intending to be limiting in any way.
  • polyene macrolide derivatives of the invention may be synthesized according to well-known methods using well-known chemistries.
  • the polyene macrolide derivatives of formula (I) may be synthesized according to Scheme (I), illustrated below:
  • R 1 , R 2 , R 3 and X are as defined for structural formula (I).
  • a core polyene macrolide having a carboxyl and an amino functionality 10 is converted to the corresponding ester, thioester or amide 12 (depending upon the identity of X) using standard methods that are well known in the art.
  • Ester, thioester or amide 12 is reacted with a reducing carbohydrate 13, for example one of the reducing carbohydrates listed in TABLE 1, supra, under Amadori rearrangement conditions to yield polyene macrolide derivatives according to formula (I).
  • the Amadori rearrangement reaction is described in detail in Amadori, 1955, Adv. Carbohydr. Chem. 10:169 and Hodge & Fisher, supra, both of which are incorporated herein by reference.
  • Core polyene macrolide 10 may be obtained commercially or may be isolated or synthesized according to well-known methods. Methods of synthesizing a variety of core polyene macrolides 10 are described in Beau, "Polyene Macrolides: Stereostructural Elucidation and Synthetic Studies of a Few Members," In: Recent Progress in the Chemical Synthesis of Antibiotics, pp. 135-182, Springer- Verlag, Berlin (1990), as well as the references cited therein. These methods may be routinely adapted to synthesize a wide variety of core polyene macrolides 10. Methods of isolating core polyene macrolides 10 as natural products are well-known in the art.
  • Ester, thioester or amide 12 may be obtained from core polyene macrolide 10 according to well-known methods.
  • U.S. Patent No. 4,035,567 describes a process for producing AME.
  • Processes for preparing alkyl esters of core polyene macrolide 10 are described in U.S. Patent No. 3,780,173, U.S. Patent No. 4,035,568, U.S. Patent No. 4,038,382 and U.S. Patent No. 4,365,058.
  • Specific methods for preparing alkyl esters of partricin are described in U.S. Patent No. 3,961,047.
  • ester, thioester or amide 12 may be commercially available.
  • AME is commercially available from Karykion, Princeton, NJ.
  • reducing carbohydrate 13 will depend upon the identity of the desired carbohydrate residue CH 2 -R 2 .
  • a reducing carbohydrate reactant that will yield the desired carbohydrate residue CH 2 -R 2 should be selected.
  • the principles of the Amadori rearrangement are well-known and briefly illustrated supra.
  • choosing an appropriate reducing carbohydrate 13 will be apparent to those of skill in the art.
  • Specific exemplary reducing carbohydrates 13 are provided in TABLE 1. Additional guidance can be found in Amadori, 1955, Adv. Carbohydr. Chem. 10:169, Hodge & Fisher, supra, (and the referenced cited therein) and U.S. Patent No. 5,314,999, all of which are incorporated herein by reference.
  • derivatives 12 do not have a free carboxyl group. Rather, this carboxyl has been reacted to form an ester, thioester or amide. Thus, derivatives 12 may not efficiently "self-catalyze" the Amadori rearrangement. As a consequence, it has been discovered that it is preferable to conduct the Amadori rearrangement reaction between derivative 12 and reducing carbohydrate 13 in the presence of water. While the reaction will proceed under anhydrous conditions, significantly better yields are obtained under non-anhydrous conditions. A variety of non- anhydrous solvent systems may be used for Scheme (I).
  • the solvent system should comprise about 1% (v/v) to 5% (v/v) water.
  • the proton donor may be the solvent system or it may be an added compound, as described in Hodge & Fisher, supra. Any of the solvent systems described in the literature may be adapted for use as described herein. Exemplary solvent systems that may be readily adapted to the principles taught herein are described in Hodge & Fisher, 1963, supra. Specific solvent systems are provided in the Examples section, infra.
  • the literature reports that the Amadori rearrangement may be successfully performed with a 1:1 molar ratio of compounds 12 and 13. However, the Applicants have discovered that using a 1:2 molar ratio of compounds 12 and 13 increases the reaction yield. Thus, while the Amadori rearrangement reaction illustrated in Scheme (I) may be performed with 1-2 equivalents of reducing carbohydrate 13, using 2 equivalents of reducing carbohydrate 13 is preferred.
  • polyene macrolide derivatives of the invention exhibit significant antifungal activity. Indeed, some of the polyene macrolide derivatives according to formula (I) exhibit significantly higher antifungal activity than both AmB and AME.
  • active polyene macrolide derivatives of the invention are identified using in vitro screening assays that are well-known in the art. Specific in vitro screening assays that can be used to assess activity are provided in the Examples section.
  • polyene macrolide derivatives of the invention may be assessed for antifungal activity using in vivo models. Again, such models are well-known in the art. Other assays as are well known in the art, or that will become apparent to those having skill in the art upon review of this disclosure, may also be used to identify active polyene macrolide derivatives of the invention.
  • active polyene macrolide derivatives of the invention will exhibit minimum inhibitory concentrations (MICs) of less than about 64 ⁇ g/mL, usually less than about 32 ⁇ g/mL, preferably less than about 16 ⁇ g/mL and most preferably less than about 4 ⁇ g/mL against Candida albicans using standard methods. Of course, compounds having MICs on the low end of these ranges, or even lower, are preferred. Most preferred for use in treating or preventing systemic infections are polyene macrolide derivatives that exhibit significant antifungal activity, high water-solubility and low toxicity. Toxicity is less of a concern for typical administration, as is water solubility.
  • polyene macrolide derivatives of the present invention have significant advantages over currently available polyene macrolide antifungals. Specifically, the polyene macrolide derivatives of the present invention show excellent water solubility, low toxicity, and effective therapeutic potency. Moreover, these glycosyl AME derivatives exhibit antifungal activity comparable to AmB in both in vitro and in vivo assays, and quite unexpectedly have a higher therapeutic index.
  • polyene macrolide derivatives according to the invention can be used in a wide variety of applications to inhibit the growth of or kill fungi.
  • the polyene macrolide derivatives can be used as disinfectants or as preservatives for materials such as foodstuffs, cosmetics, medicaments and other nutrient-containing materials.
  • the polyene macrolide derivatives can be added to the desired material singly, as mixtures of several polyene macrolide derivatives or in combination with other antifungal and/or antimicrobial agents.
  • the polyene macrolide derivatives may be supplied as the compound per se or may be in admixture with a variety of carriers, diluents or excipients as are well known in the art.
  • polyene macrolide derivatives of the invention can be administered or applied singly, as mixtures of two or more polyene macrolide derivatives, in combination with other antifungal, antibiotic or antimicrobial agents or in combination with other pharmaceutically active agents.
  • the polyene macrolide derivatives can be administered or applied per se or as pharmaceutical compositions.
  • the specific pharmaceutical formulation will depend upon the desired mode of administration, and will be apparent to those having skill in the art. Numerous compositions for the topical or systemic administration of polyene macrolides are described in the literature. Any of these compositions may be formulation with the polyene macrolide derivatives of the invention.
  • compositions comprising the polyene macrolide derivatives of the invention may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active polyene macrolide derivatives into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • polyene macrolide derivatives of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. :
  • the polyene macrolide derivatives of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • the solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the polyene macrolide derivatives may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • the polyene macrolide derivatives can be readily formulated by combining them with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
  • disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oilsj alcohols, etc. Additionally, flavoring agents, preservatives, coloring agents and the like may be added.
  • compositions may take the form of tablets, lozenges, etc. formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories
  • the polyene macrolide derivatives may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • Liposomes and emulsions are well known examples of delivery vehicles that may be used to deliver the polyene macrolide derivatives of the invention.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the polyene macrolide derivatives may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
  • the polyene macrolide derivatives of the invention may be acidic or basic
  • the polyene macrolide derivatives may be included in any of the above-described formulations as the free acids, the free bases or as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are those salts which retain substantially the antifungal activity of the free acids or bases and which are prepared by reaction with bases or acids, respectively. Pharmaceutical salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free base or acid forms.
  • salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfiiric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as amino acids (e.g., aspartic acid, glutamic acid, asparagine, glutamine, lysine, orthinine) acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyravic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benz
  • pharmaceutically acceptable salts are formed with aspartic acid, glutamic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid and mandelic acid, more preferably, with aspartic acid, glutamic acid, and fumaric acid and most preferably with aspartic acid.
  • the aspartate salt of a compound of structural formula (I) is formed. '
  • polyene macrolide derivatives of the invention or compositions thereof, will generally be used in an amount effective to achieve the intended purpose.
  • amount used will depend on the particular application.
  • an antifungally effective amount of a polyene macrolide derivative, or composition thereof is applied or added to the material to be disinfected or preserved.
  • antifungally effective amount is meant an amount of polyene macrolide derivative or composition that inhibits the growth of, or is lethal to, a target fungi. While the actual amount will depend on a particular target fungi and application, for use as a disinfectant or preservative the polyene macrolide derivatives, or compositions thereof, are usually added or applied to the material to be disinfected or preserved in relatively low amounts.
  • the polyene macrolide derivative comprises less than about 5% by weight of the disinfectant solution or material to be preserved, preferably less than about 1% by weight and more preferably less than about 0.1 % by weight.
  • the polyene macrolide derivative comprises less than about 5% by weight of the disinfectant solution or material to be preserved, preferably less than about 1% by weight and more preferably less than about 0.1 % by weight.
  • the polyene macrolide derivatives of the invention, or compositions thereof are administered or applied in a therapeutically effective amount.
  • therapeutically effective amount is meant an amount effective ameliorate the symptoms of, or ameliorate, treat or prevent fungal infections. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective dose can be determined using, for example, the in vitro assays provided in the examples.
  • the treatment may be applied while the infection is visible, or even when it is not visible. Nn ordinarily skilled artisan will be able to determine therapeutically effective amounts to treat topical infections without undue experimentation.
  • a therapeutically effective dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models to achieve a circulating polyene macrolide derivative concentration range that includes the I 50 as determined in cell culture (i.e., the concentration of test compound that is lethal to 50% of a cell culture), the MIC, as determined in cell culture (i.e., the minimal inhibitory concentration for growth) or the I 100 as determined in cell culture (i.e., the concentration of polyene macrolide derivative that is lethal to 100% of a cell culture).
  • the I 50 as determined in cell culture
  • the MIC the concentration of test compound that is lethal to 50% of a cell culture
  • the I 100 as determined in cell culture
  • Such information can be used to more accurately determine useful doses in humans.
  • Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art can readily optimize administration to humans based on animal data. Alternatively, initial dosages can be determined from the dosages administered of known polyene macrolides by comparing the IC 50 , MIC and/or I ⁇ 00 of the specific polyene macrolide derivative with that of a known polyene macrolide, and adjusting the initial dosages accordingly. The optimal dosage may be obtained from these initial values by routine optimization.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active polyene macrolide derivative which are sufficient to maintain therapeutic effect.
  • Usual patient dosages for administration by injection range from about 0.1 to 5 mg/kg/day, preferably from about 0.5 to 1 mg/kg/day.
  • Therapeutically effective serum levels may be achieved by administering multiple doses each day.
  • the effective local concentration of polyene macrolide derivative may not be related to plasma concentration.
  • One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • the amount of polyene macrolide derivative administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the antifungal therapy may be repeated intermittently while infections are detectable or even when they are not detectable.
  • the therapy may be provided alone or in combination with other drugs, such as for example other antifungals, antibiotics or antimicrobials, or other polyene macrolide derivatives of the invention.
  • a therapeutically effective dose of the polyene macrolide derivatives described herein will provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of the polyene macrolide derivatives can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) or the LD 100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Polyene macrolide derivatives which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in human.
  • the dosage of the polyene macrolide derivatives described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See, e.g., Fingl et al, 1975, In: The Pharmacological Basis of Therapeutics, Ch.l, p.l.
  • 1-2 equivalents of the reducing sugar (13) may be used per equivalent of polyene macrolide derivative (12). However, it has been found that using 2 equivalents provides better yields.
  • the solutions were precipitated with ether and washed with ether 3 times.
  • the product was refrigerated for approximately 60 hours to allow the product to dry.
  • the product was then lyophilized, and HPLC analysis was conducted for each product.
  • the compounds produced in group C are identified as C1-C4 and correspond to compounds C1-C4 given in the text above as preferred compounds of the present invention.
  • Compounds in group B are identified as B1-B4, and compounds from group A are identified as A1-A4.
  • HPLC analyses were conducted using an HP 1090 analytical HPLC (Waters Symmetry C-18, particle size 3.5 ⁇ m, 4.6 x 50 mm, Cat. No. WAT200625) using a linear gradient of 35% to 55% Solvent B (100 mM Triethylammonium acetate in 90% acetonitrile pH 7) in Solvent A (100 mM Triethylammonium acetate pH 7) over 10 minutes at a flow rate of 1.1 mL/min. HPLC peaks were observed by UV. The retention times of the peaks are provided in TABLE 3.
  • Minimum Inhibitory Concentrations were determined as described in Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard; NCCLS document M27-A (ISBN 1-56238-328-0); NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087, 1997. Also, Minimum Fungicidal Concentrations (MFC) were made using material obtained from the well defining the MIC and at least 3 compound dilutions lower than the MIC. Ten microliter samples were removed from the corresponding wells and deposited onto blood agar plates. Plates were incubated at 35 °C for 48 hours. The highest compound dilution at which no colonies are apparent on the plate was considered the MFC.
  • MFC Minimum Fungicidal Concentrations
  • NLD non- lethal dose
  • TABLE 3 shows the results from these tests, where compounds from group C in TABLE 2 are listed as C1-C4, compounds from group B are listed as B1-B4, and compounds from group A are listed as A1-A4. Data are also shown for AmB and AME for comparison.
  • compounds C1-C4 are compounds of the present invention and as shown in TABLE 3, these compounds exhibit surprisingly superior results than AmB and AME.
  • Compounds C1-C4 exhibit higher MICs and NLDs than AME and extremely higher MICs and NLDs than AmB.
  • Compounds C1-C4 also exhibit higher water solubility than AME and extremely higher water solubility than AmB.
  • the compounds have comparable antifungal activity to AmB, they exhibit better therapeutic indices.
  • FIG. 1 shows the level of Candida albicans in the kidneys of mice treated with various compounds of the present invention. As shown the concentration of Candida albicans is significantly lower in those mice treated compounds Cl and C2 than for AME.
  • mice were administered selected compounds, or the comparative compound AmB, by intravenous injection once daily on study days 1 through 5 and study days 8 through 12 (a total of 10 days) to evaluate subchronic toxicity.
  • the dosages typically ranged from 5 to 30 mg/kg/day and each dose group consisted of 5 to 10 mice.
  • Clinical observations and body weights were recorded at scheduled intervals. Mice were sacrificed at the completion of treatment and the kidneys were preserved for histopathologic examination. The maximum no-observed-adverse-effect level (“NOAEL”) was determined on the basis of clinical and histopathologic findings. Results are tabulated in TABLE 4.
  • polyene macrolide derivatives of the invention particularly, the aspartic acid salts thereof, of posses good water solubility.
  • Compounds with good water solubility i.e., aspartate salts
  • polyene macrolide derivatives do not exhibit the same degree of water solubility and thus were dissolved in a 0.1% lactic acid solution at pH of about 2.0.
  • propylene glycol was added in small quantities (up to about 10% (v/v)) if the polyene macrolide derivative did not dissolve in the lactic acid.

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Abstract

La présente invention concerne une nouvelle classe de dérivés de macrolides de polyène s'utilisant dans le traitement ou la prévention d'infections fongiques. Ces nouveaux dérivés de macrolides de polyène présentent une activité antifongique et une solubilité dans l'eau nettement supérieures à celles de l'ester méthylique d'amphotéricine B (AME). En outre, ces nouveaux dérivés de macrolides de polyène présentent une meilleure solubilité dans l'eau et une moindre toxicité, aussi bien par rapport à l'amphotéricine B (AmB) que l'AME.
PCT/US2001/001294 2000-01-14 2001-01-16 Derives de macrolides de polyene, preparation et utilisations correspondantes WO2001051061A1 (fr)

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EP01903072A EP1278527A4 (fr) 2000-01-14 2001-01-16 Derives de macrolides de polyene, preparation et utilisations correspondantes
CA002394833A CA2394833A1 (fr) 2000-01-14 2001-01-16 Derives de macrolides de polyene, preparation et utilisations correspondantes
AU30935/01A AU780724B2 (en) 2000-01-14 2001-01-16 Derivatives of polyene macrolides and preparation and use thereof
JP2001551485A JP2003519662A (ja) 2000-01-14 2001-01-16 ポリエン・マクロライド誘導体並びにその製法及び使用

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WO2003070174A2 (fr) 2002-02-15 2003-08-28 Sympore Gmbh Conjugues de composes biologiquement actifs, procedes de preparation et d'utilisation, et formulation et applications pharmaceutiques
WO2009015541A1 (fr) * 2007-07-30 2009-02-05 Shanghai Institute Of Pharmaceutical Industry Antibiotiques à base de diesters de polyènes
US9447136B2 (en) 2012-03-09 2016-09-20 Blirt S.A. Semisynthetic derivatives of Nystatin A1
KR20170016957A (ko) 2014-06-12 2017-02-14 시오노기 앤드 컴파니, 리미티드 폴리엔 마크로라이드 유도체
US9745335B2 (en) 2012-06-15 2017-08-29 Blirt S.A. N-substituted second generation derivatives of antifungal antibiotic amphotericin B and methods of their preparation and application
WO2020160443A1 (fr) 2019-01-31 2020-08-06 Sigma-Aldrich Co. Llc Agents antifongiques ayant une solubilité aqueuse améliorée
CN113773355A (zh) * 2021-08-23 2021-12-10 湖南省微生物研究院 一种多烯大环内酯类化合物及其制备方法和应用

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AU2006274197A1 (en) * 2005-07-26 2007-02-01 Merckle Gmbh Macrolide conjugates of pyrrolizine and indolizine compounds as inhibitors of 5-lipooxygenase and cyclooxygenase
US7825143B2 (en) * 2007-07-10 2010-11-02 Montana State University - Billings Method for controlling the yeast-to-filamentous growth transition in fungi
WO2020119773A1 (fr) * 2018-12-13 2020-06-18 上海医药工业研究院 Dérivé peptidique de l'amphotéricine b

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EP1313487A4 (fr) * 2000-05-31 2006-01-11 Migenix Inc Derives amides hydrosolubles de macrolides polyenes et leur preparation et utilisation
EP1313487A1 (fr) * 2000-05-31 2003-05-28 IntraBiotics Pharmaceuticals, Inc. Derives amides hydrosolubles de macrolides polyenes et leur preparation et utilisation
WO2003070174A2 (fr) 2002-02-15 2003-08-28 Sympore Gmbh Conjugues de composes biologiquement actifs, procedes de preparation et d'utilisation, et formulation et applications pharmaceutiques
WO2009015541A1 (fr) * 2007-07-30 2009-02-05 Shanghai Institute Of Pharmaceutical Industry Antibiotiques à base de diesters de polyènes
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KR20170016957A (ko) 2014-06-12 2017-02-14 시오노기 앤드 컴파니, 리미티드 폴리엔 마크로라이드 유도체
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WO2020160443A1 (fr) 2019-01-31 2020-08-06 Sigma-Aldrich Co. Llc Agents antifongiques ayant une solubilité aqueuse améliorée
CN113773355A (zh) * 2021-08-23 2021-12-10 湖南省微生物研究院 一种多烯大环内酯类化合物及其制备方法和应用
CN113773355B (zh) * 2021-08-23 2023-03-10 湖南省微生物研究院 一种多烯大环内酯类化合物及其制备方法和应用

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